Pancreatic Ductal Adenocarcinoma (PDAC), which comprises 85% of pancreatic cancers, is the 4th leading cause of cancer death in the United States with a 5-year survival of 6%. PDAC tumors are often desmoplastic, with marked inflammatory infiltrates and dysregulated immune responses. Interferons (IFNs), key mediators of the innate immune response, act by binding to specific cell-surface receptors, activating the JAK-STAT1 pathway, and inducing the expression of numerous genes involved in the response to infection, most notably from viruses. While IFNs are most well-known for this anti-viral role, recently, an interferon-related DNA damage resistance signature (IRDS) consisting of genes induced by unphosphorylated STAT1 (U-STAT1) was found to confer resistance to genotoxic stress in cancer. Our laboratory recently established a genetically engineered mouse model (GEMM) of PDAC in which oncogenic Kras is combined with deleted Rb1 in the pancreas due to Cre-mediated recombination (KRC mice). By array analysis of cancer cells derived from this GEMM, we determined that they exhibit a strong IRDS. To extrapolate this finding to human PDAC tumors, I clustered RNA- Seq data from The Cancer Genome Atlas and found that 41.3% of PDAC patients also possess this IRDS signature. Therefore, the STAT1-IRDS pathway could be important in PDAC pathobiology. Accordingly, I plan to test the central hypothesis that the STAT1-IRDS pathway contributes in a crucial manner to chemo- and radio-resistance in PDAC patients with an IRDS signature, and that the pathway could serve as a beneficial therapeutic target in these patients. To test this hypothesis pre-clinically, I propose a combined mechanistic and informatics based approach which involves the following specific aims. 1) Using gene expression, classify GEMMs or human pancreatic cancer cell lines as being IRDS (+) or (-) and determine whether IRDS status correlates with the presence of U-STAT1 in tumors as revealed by immunohistochemical staining. 2) Determine if knockout of the STAT1 gene in murine and human pancreatic cancer cell lines is beneficial or harmful both in cells and orthotopic models and whether it depends on IRDS status. 3) Identify chemo- and radio-resistant genes downstream of STAT1. Collectively, this research will determine if the STAT1-IRDS pathway is a novel therapeutic target in pancreatic cancer patients with an IRDS signature at the pre-clinical level and will serve as a proof of concept for future clinical development.